The human heart wall consists of an inner layer of simple squamous epithelium, referred to as the endocardium, overlying a variably thick heart muscle or myocardium and is enveloped within a multi-layer tissue structure referred to as the pericardium. The innermost layer of the pericardium, referred to as the visceral pericardium or epicardium, clothes the myocardium. The epicardium reflects outward at the origin of the aortic arch to form an outer tissue layer, referred to as the parietal pericardium, which is spaced from and forms an enclosed sac extending around the visceral pericardium of the ventricles and atria. An outermost layer of the pericardium, referred to as the fibrous pericardium, attaches the parietal pericardium to the sternum, the great vessels and the diaphragm so that the heart is confined within the middle mediastinum. Normally, the visceral pericardium and parietal pericardium lie in close contact with each other and are separated only by a thin layer of a serous pericardial fluid that enables friction free movement of the heart within the sac. The space (really more of a potential space) between the visceral and parietal pericardia is referred to as the pericardial space. In common parlance, the visceral pericardium is usually referred to as the epicardium, and epicardium will be used hereafter. Similarly, the parietal pericardium is usually referred to as the pericardium, and pericardium will be used hereafter in reference to parietal pericardium.
Access to the pericardial space is desirable in order to provide a variety of cardiac therapies, including delivery of therapeutic agents (defined herein as including genetic agents, biologic agents, and pharmacologic agents), placement of electrical medical leads for pacing, cardioversion, defibrillation or EGM monitoring, removal of pericardial fluid for diagnostic analysis, or other purposes (e.g. placement of chemical sensors). A variety of mechanisms have been developed for accessing the pericardial space, ranging from a simple puncture by means of a large bore needle to intricate catheter or cannula based systems provided with sealing and anchoring mechanisms.
Access to the pericardial space may be accomplished from outside the body by making a thoracic or sub-xiphoid incision to access and cut or pierce the pericardial sac. Access to the pericardial space from the exterior of the body, accomplished by passing a cannula or catheter type device through the chest wall and thereafter passing the cannula or catheter or a further instrument through the pericardium into the pericardial space, is disclosed in U.S. Pat. Nos. 5,827,216, 5,900,433, and 6,162,195 issued to Igo, U.S. Pat. No. 5,336,252 issued to Cohen, and U.S. Pat. Nos. 5,972,013, 6,206,004, 6,592,552 by Schmidt, for example. In certain cases the pericardial sac is cut by a cutting instrument as disclosed in U.S. Pat. Nos. 5,931,810, 6,156,009, and 6,231,518 issued to Grabek et al.
Alternatively, an elongated perforating instrument device is introduced from a skin incision or puncture by a transvenous or transarterial approach into the right or left heart chambers, respectively, and a cutting or piercing or penetrating mechanism at the distal end of the elongated perforating instrument is operated to penetrate through the atrial or ventricular wall of the right or left heart chamber into the surrounding pericardial space without perforating the pericardial sac. For example, a transvenous catheter provided with a hollow helical needle adapted to rotated and pierce through the wall of a right or left heart chamber to access the pericardial space to deliver pharmacologic agents is disclosed in U.S. Pat. No. 5,797,870 issued to March et al. A transvenous catheter introduced into the right ventricular chamber to provide access through the right ventricular wall to enable passage of an electrical medical lead into the pericardial space is disclosed in, U.S. Pat. No. 4,991,578 issued to Cohen, and U.S. Pat. No. 5,330,496 issued to Alferness, for example. It has also been proposed that a preferred site of penetration of catheters or electrical medical leads through the atrial wall into the pericardial space is within the right atrial appendage as disclosed in U.S. Pat. No. 5,269,326 issued to Verrier, U.S. Pat. No. 6,200,303 issued to Verrier et al and U.S. Pat. No. 5,968,010 issued to Waxman et al. Transvenous approaches through either of the inferior vena cava or the superior vena cava are disclosed in these patents.
It would be particularly desirable to facilitate access to the pericardial space to enable chronic delivery of pharmacologic agents to the heart as suggested in the above-referenced '326, '303, and '010 patents. In particular it is noted that the pericardial fluid provides an excellent medium for delivery of pharmacologic agents to the cardiac muscles and coronary vessels without distribution to other organs. Among the clinically significant pharmacologic agents (i.e., drugs) which could advantageously be delivered to the heart via the pericardial fluid are those that improve cardiac contractility (e.g., digitalis drugs, adrenergic agonists, etc.), that suppress arrhythmias (e.g., class I, II, III, and IV agents and specialized drugs such as amiodarone, which is particularly potent but has severe systemic side effects), that dilate coronary arteries (e.g., nitroglycerin, calcium channel blockers, etc.), that lyse clots in the coronary circulation (e.g., thrombolytic agents such as streptokinase or tissue-type plasminogen activator (TPA)) or that reverse symptoms of heart failure (e.g. beta-adrenergic blockers).
Examples of other pharmacologic agents which may be administered into the pericardial space include: agents to protect the heart pharmacologically from the toxic effects of drugs administered to the body generally for other diseases, such as cancer; antibiotics, steroidal and non-steroidal medications for the treatment of certain pericardial diseases; and growth factors to promote angiogenesis or neovascularization of the heart.
The delivery of further pharmacologic agents into the pericardial space is disclosed in the above-referenced '433 patent, wherein cardio-active or cardio-vascular active drugs are selected from vasodilator, antiplatelet, anticoagulant, thrombolytic, anti-inflammatory, antiarrhythmic, initropic, antimitotic, angiogenic, antiatherogenic and gene therapy bioactive agents. The approaches to the pericardial space include those disclosed in the above-referenced '326 patent or transthoracically, e.g., under the xiphoid process, i.e., by a sub-xiphoid surgical approach.
It is proposed in the '433 patent to deliver the pharmacologic agents into the pericardial space to treat or to prevent vascular thrombosis and angioplasty restenosis, particularly coronary vascular thrombosis and angioplasty restenosis, thereby to decrease incidence of vessel rethrombosis, unstable angina, myocardial infarction, and sudden death. In particular, it is proposed to deliver a congener of an endothelium-derived bioactive agent, more particularly a nitrovasodilator, representatively the nitric oxide donor agent sodium nitroprusside, to the pericardial space at a therapeutically effective dosage rate to abolish cyclic coronary flow reductions (CFR's) while reducing or avoiding systemic effects such as suppression of platelet function and bleeding. Particular congeners of an endothelium-derived bioactive agent include prostacyclin, prostaglandin E1, and a nitrovasodilator agent. Nitrovasodilater agents include nitric oxide (NOX) and NOX donor agents, including L-arginine, sodium nitroprusside and nitroglycycerine. The so-administered nitrovasodilators are effective to provide one or more of the therapeutic effects of promotion of vasodilation, inhibition of vessel spasm, inhibition of platelet aggregation, inhibition of vessel thrombosis, and inhibition of platelet growth factor release, at the treatment site, without inducing systemic hypotension or anticoagulation. The administration of nitroglycerin intravenously has been demonstrated to reduce infarct size, expansion and complications in patients (Circulation. 1988 October; 78(4):906-19).
As set forth in commonly assigned U.S. Pat. No. 6,115,630 to Stadler et al, myocardial ischemia is a leading cause of human morbidity and mortality in developed countries. Myocardial ischemia involves oxygen starvation of the myocardium, particularly in the bulky left ventricular wall, which can lead to myocardial infarction and/or the onset of malignant arrhythmias if the oxygen starvation is not alleviated. Although myocardial ischemia is associated with the symptom of angina pectoris, the majority of episodes of myocardial ischemia are asymptomatic or “silent.” Myocardial ischemia is caused by an imbalance of oxygen supply and oxygen demand. The diseased arteries are pathohistologically characterized by constriction in one or more section of a cardiac artery that is caused by vessel thrombosis, platelet aggregation, vessel spasm, angioplasty restenosis, and other conditions. This can cause to decreased oxygen supply, while exercise, stress or other conditions leading to increased tone of the sympathetic nervous system and/or increased blood levels of catecholamines can increase myocardial oxygen demand. As noted in the '630 patent, accurate and rapid detection of myocardial ischemia is the first essential step toward reducing morbidity and mortality from this often silent but deadly condition. Without the knowledge of the condition, it cannot be treated.
An ischemic event often causes the performance of the heart to be impaired and manifests itself through changes in the electrical (e.g. the electrocardiogram or EGM signal), functional (e.g., pressure, flow, etc.) or metabolic (e.g. blood or tissue oxygen, pH, etc.) parameters of the cardiac function. An ischemic event results in changes in the electrophysiological properties of the heart muscle that eventually manifest themselves as changes in the external ECG or internal EGM. The conventional approach to the detection of ischemia and infarction relies on analysis and interpretation of features of the ECG or EGM, e.g., the ST-segment, the T-wave or the Q-wave, to detect deviations from normal. Computer-based technology has been employed to monitor, display, and semi-automatically or automatically analyze the ischemic ECG changes. The above-referenced '630 patent sets forth improved methods of detecting ischemia from the EGM sensed across a plurality of sense electrodes.
In commonly assigned U.S. Pat. No. 5,199,428 to Obel et al, it is proposed that the detection of myocardial ischemia can be accomplished by sensing the patient's coronary sinus blood pH and/or oxygen saturation and comparing each to preset, normal thresholds. Blood pH or oxygen saturation sensors are located in the coronary sinus or a coronary vein to measure the dissolved oxygen and/or the lactic acid level of myocardial venous return blood. The measured blood oxygen saturation and/or blood pH and the ST segment deviation are compared to respective programmable thresholds reflecting clinical risk levels. When ischemia is confirmed, the disclosed system triggers burst stimulation of selected nerves until the measured blood gas and/or blood pH and/or ST segment returns to non-clinical risk levels.
For example, it has been proposed, as described in commonly assigned, co-pending U.S. patent application Ser. No. 10/002,338 filed Oct. 30, 2001, and Publication No. 2003/0083702 to employ various types of sensors including accelerometers, magnets, and sonomicrometers typically located in a blood vessel or heart chamber that respond to or move with mechanical heart function to derive a metric that changes in value over the heart cycle in proportion to the strength, velocity or range of motion of one or more of the heart chambers or valves. Such a mechanical function metric would complement the measurement of blood pressure and the EGM to more confidently determine the degree of change in a heart failure (HF) condition of the heart.
An implantable EGM monitor for recording the cardiac electrogram from electrodes remote from the heart as disclosed in commonly assigned U.S. Pat. No. 5,331,966 and PCT publication WO 98/02209 is embodied in the Medtronic® REVEAL® Insertable Loop Recorder having spaced housing EGM electrodes. More elaborate implantable hemodynamic monitors (IHMs) for recording the EGM from electrodes placed in or about the heart and other physiologic sensor derived signals, e.g., one or more of blood pressure, blood gases, temperature, electrical impedance of the heart and/or chest, and patient activity have also been proposed. In particular, the Medtronic® CHRONICLE® Implantable Hemodynamic Monitor (IHM) system comprises a CHRONICLE® Model 9520 IHM of the type described in commonly assigned U.S. Pat. No. 5,368,040 coupled with a Model 4328A pressure sensor lead that monitors the EGM of the heart and senses blood pressure within a heart chamber using a pressure sensing transducer of the type disclosed in commonly assigned U.S. Pat. No. 5,564,434. The CHRONICLE® Model 9520 IHM measures absolute blood pressure, and the patient is also provided with an externally worn Medtronic® Model No. 2955HF atmospheric pressure reference monitor of the type described in commonly assigned U.S. Pat. No. 5,810,735 to record contemporaneous atmospheric pressure values.
A further IHM is disclosed in commonly assigned U.S. Pat. No. 6,438,408 that measures a group of parameters indicative of the state of HF employing EGM signals, measures of blood pressure including absolute pressure P, developed pressure DP (DP=systolic P—diastolic P), and/or dP/dt, and measures of heart chamber volume (V) over one or more cardiac cycles. These parameters include: (1) relaxation or contraction time constant tau (τ); (2) mechanical restitution (MR), i.e., the mechanical response of a heart chamber to premature stimuli applied to the heart chamber; (3) recirculation fraction (RF), i.e., the rate of decay of PESP effects over a series of heart cycles; and (4) end systolic elastance (EES), i.e., the ratios of end systolic blood pressure P to volume V. These HF state parameters are determined periodically regardless of patient posture and activity level. However, certain of the parameters are only measured or certain of the data are only stored when the patient heart rate is regular and within a normal sinus range between programmed lower and upper heart rates. The parameter data is associated with a date and time stamp and with other patient data, e.g., patient activity level, and the associated parameter data is stored in IMD memory for retrieval at a later date employing conventional telemetry systems. Incremental changes in the parameter data over time, taking any associated time of day and patient data into account, provide a measure of the degree of change in the HF condition of the heart.
Methods and apparatus for developing estimates of the ventricular afterload derived from ventricular pressure measurements employing the CHRONICLE® Model 9520 IHM coupled with a Model 4328A pressure sensor lead are described in commonly assigned, co-pending U.S. patent application Ser. No. 10/376,064 filed Feb. 26, 2003. The estimates of the ventricular afterload can be used to quantify the current state of cardiovascular function, to discern changes in the state of cardiovascular function over time, and to select or alter a therapy delivered by an IMD to optimize cardiovascular function of patients experiencing HF, hypertension, and other clinical pathologies
A system and method are disclosed in commonly assigned co-pending U.S. patent application Ser. No. 10/368,278 filed Feb. 18, 2003, for detecting mechanical pulsus alternans (MPA) as well as associated electrical alternans and other MPA episode data from ventricular pressure and EGM measurements employing the CHRONICLE® Model 9520 IHM coupled with a Model 4328A pressure sensor lead. The collected MPA episode trend data provides indicia related to the mechanical performance of the HF patients heart so that the response of the heart to drug or electrical stimulation therapies prescribed to reduce HF symptoms can be assessed.
It has also been proposed to detect ischemic conditions of the heart from EGM characteristics, particularly, ST segment elevation, and mechanical heart motion as measured by an accelerometer or changes in measured blood pressure, for example, as described in commonly assigned, co-pending U.S. Patent Application Publication Nos. US 2003/0045805 and US 2002/0120205.
It is therefore desirable to provide a system and method that detects an ischemic state and delivers a pharmacologic agent into the pericardial space to treat the ischemic state in an efficient manner.
It would also be desirable to provide a system and method that delivers NO-donors into the pericardial space to treat detected conditions of the heart.